CSL200 Gene Therapy in Adults With Severe Sickle Cell Disease

A Phase 1 Pilot Study to Evaluate the Safety and Feasibility of Gene Therapy With CSL200 (Autologous Enriched CD34+ Cell Fraction That Contains CD34+ Cells Transduced With Lentiviral Vector Encoding Human γ-GlobinG16D and Short-Hairpin RNA734) in Adult Subjects With Severe Sickle Cell Disease

This is a phase 1 pilot study of CSL200 in adult subjects with severe sickle cell disease. The primary objectives of this study are to evaluate the safety of the following: collection of CD34+ hematopoietic stem / progenitor cells by apheresis after mobilization with plerixafor, reduced intensity conditioning with melphalan, and administration of CSL200.

Study Overview

• Status: Terminated
• Conditions: Anemia, Sickle Cell
• Intervention / Treatment: Biological: Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of sickle cell disease with the homozygous HbS homozygous genotype (HbSS) or an HbSβ thalassemia variant (ie, HbSβ0 thalassemia or HbSβ+ thalassemia) genotype, confirmed by hemoglobin studies.
• Fetal hemoglobin (HbF) ≤ 15%.

• Severe sickle cell disease symptomatology, defined as any one or more of the following:

  1. ≥ 2 episodes of acute chest syndrome in the last 2 years.
  2. ≥ 3 episodes of severe pain events requiring a visit to a medical facility and treatment with opioids in the last 2 years.
  3. > 2 episodes of recurrent priapism in the last 2 years.
  4. Red-cell alloimmunization (> 2 antibodies) during long-term transfusion therapy (lifetime history).
  5. Chronic transfusions for primary or secondary prophylaxis (lifetime history).
  6. Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet velocity ≥ 2.7 m/sec (lifetime history).
  7. Clinically significant neurologic event (eg, ischemic stroke) or any neurological deficit lasting > 24 hours.
• Not eligible for human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation, defined as follows: no medically eligible, available, and willing 10/10 matched HLA-identical sibling donor, unless subject has declined this treatment option (as documented in the informed consent form).
• Not eligible for, declined, or, as judged by the investigator, failed therapy with hydroxyurea and if still on hydroxyurea is able to interrupt hydroxyurea starting at the beginning of the transfusions, before mobilization and apheresis.

Exclusion Criteria:

• Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency.
• Thiopurine S-methyltransferase (TPMT) deficiency.
• Alpha thalassemia.

• Inadequate bone marrow function, defined as at least 1 of the following:

  1. Absolute neutrophil count < 1000/µL.
  2. Platelet count < 120,000/µL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CSL200; Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734

Biological: Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734; Cryopreserved formulated autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734 in a bag for infusion; Plerixafor to mobilize hematopoietic stem cells prior to each apheresis; Single dose melphalan before administration of CSL200; Other Names: CSL200

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) associated with the administration of CSL200	Adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is medically significant. Adverse event of special interest (AESI) is defined in this study as any of the following: acute immune reactions, autoimmunity to CSL200; malignancy; predominant integration site in presence of malignancy or other abnormality.	Up to 48 weeks
Number of subjects experiencing AEs, SAEs, and AESIs associated with the administration of CSL200		Up to 48 weeks
Number of AEs, SAEs, and AESIs associated with the collection of CD34+ HSPCs by apheresis after mobilization with plerixafor		Up to 6 weeks
Number of subjects experiencing AEs, SAEs, and AESIs associated with the collection of CD34+ HSPCs by apheresis after mobilization with plerixafor		Up to 6 weeks
Number of AEs, SAEs, and AESIs associated with reduced intensity conditioning with melphalan		Up to 3 weeks
Number of subjects experiencing AEs, SAEs, and AESIs associated with reduced intensity conditioning with melphalan		Up to 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total by-subject number of CD34+ HSPCs collected in total and in each apheresis session	Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by CD34+ HSPCs collected	Up to 2 days
Number of subjects receiving plerixafor and number of plerixafor doses administered by subject	Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by plerixafor administrations	Up to 2 days
Number of subjects undergoing apheresis and number of apheresis sessions by subject	Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by apheresis sessions	Up to 2 days
The number of subjects undergoing reduced intensity conditioning with melphalan and able to receive CSL200	Reduced intensity conditioning assessed by subjects receiving melphalan	2 days
Number of subjects receiving CSL200		1 day
By-subject number of separate CSL200 drug products administered		1 day
Number of CSL200 CD34+ HSPCs/kg administered by subject and by CSL200 drug product		1 day
By-subject total number and percentage of CD34+ HSPCs transduced with CAL-H		Up to 48 weeks
Vector copy number (VCN)	VCN will be determined by using the average number of CAL-H vector genomes per cell	Up to 48 weeks

Collaborators and Investigators

• Sponsor: CSL Behring

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2019
• Primary Completion (Actual): May 5, 2021
• Study Completion (Actual): May 5, 2021

Study Registration Dates

• First Submitted: September 13, 2019
• First Submitted That Met QC Criteria: September 13, 2019
• First Posted (Actual): September 17, 2019

Study Record Updates

• Last Update Posted (Actual): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 14, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: CSL200_1001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

CSL will consider requests to share Individual Patient Data (IPD) from systematic review groups or bona-fide researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com.

Applicable country specific privacy and other laws and regulations will be considered and may prevent sharing of IPD.

If the request is approved and the researcher has executed an appropriate data sharing agreement, IPD that has been appropriately anonymized will be available.

• IPD Sharing Time Frame: IPD requests may be submitted to CSL no earlier than 12 months after publication of the results of this study via an article made available on a public website.

IPD Sharing Access Criteria

Requests may only be made by systematic review groups or bona-fide researchers whose proposed use of the IPD is non-commercial in nature and has been approved by an internal review committee.

An IPD request will not be considered by CSL unless the proposed research question seeks to answer a significant and unknown medical science or patient care question as determined by CSL's internal review committee.

The requesting party must execute an appropriate data sharing agreement before IPD will be made available.

• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No